The hippocampus plays an important role in a number of normal physiological processes and in pathological conditions, including Alzheimer's disease and epilepsy. Development of a complete understanding of the molecular and cellular mechanisms of regulation of synaptic function in the hippocampus could lead to new strategies for treatment of these disorders. Until recently, it was thought that all of the actions of glutamate, the major excitatory neurotransmitter in the hippocampus, were mediated by activation of ligand-gated cation channels. However, it is now clear that glutamate also activates metabotropic glutamate receptors (mGluRs), that are coupled to effector systems through GTP binding proteins. mGluRs play a number of important roles in regulating cell excitability and synaptic transmission in the hippocampus. However, the precise physiological roles of the different mGluR subtypes are not known. A complete understanding of both normal and pathological hippocampal function will require a detailed understanding of the roles of mGluRs in regulating hippocampal physiology. Eight mGluR subtypes have been cloned and these receptors have been classified into three major groups. Many of the physiolological roles of group I mGluRs (mGluR1 and mGluR5) in the hippocampus have been defined, but less is known about the physiological roles of the group II (mGluR2 and mGluR3) and group III (mGluRs 4, 6, 7, and 8) mGluRs. A series of studies is proposed that is aimed at determining the localization and physiological roles of group II and group III mGluRs in the hippocampus and the cellular mechanisms by which activation of these receptors modulates hippocampal function. Patch clamp recordings in hippocampal slices and studies of mGluR pharmacology in expression systems will be used to test the hypothesis that a group II mGluR serves as an autoreceptor at the perforant path synapses. mGluR2 and mGluR3-specific antibodies will then be used for immunocytochemistry with electron microscopy (immuno-EM) to definitively determine whether mGluR2 and/or mGluR3 is presynaptically localized at these synapses. Immuno-EM will then be used to test the hypothesis that mGluR4a is localized postsynaptically and mGluR7 presynaptically on hippocampal neurons. Patch clamp recordings in hippocampal slices and studies of mGluR4a and mGluR7 pharmacology in expression systems will then be used to test the hypothesis that these receptors play distinct pre- and postsynaptic roles in the hippocampus. In addition to advancing our knowledge of hippocampal function, these studies will lead to a more complete understanding of the physiology and pharmacology of the mGluR family. Glutamate is the major excitatory neurotransmitter in the central nervous system and glutamatergic synapses are widespread throughout the brain. Thus, the mGluRs are likely to play important roles in various aspects of brain function. Developing an understanding of the physiological roles of each mGluR subtype will ultimately lead to advances in a number of areas of neurobiology.